The age-related macular degeneration (AMD) characterized by the formation of subretinal choroidal neovascularization is the main cause of blindness in the elderly. Vascular endothelial growth factor (VEGF) regulates angiogenesis and enhances vascular permeability that results in visual acuity deterioration. Blockade of VEGF action is currently the most effective strategy in preventing choroidal angiogenesis and reducing vascular permeability. The intravitreal injection of anti-VEGF drugs has been widely employed to reduce the disease progression and improve the visual outcomes of the affected patients. Unfortunately, intravitreal injection requires the administration in hospital, poses a risk of sevee infection, retinal detachment, cataract, endophthalmitis, intraocular inflammation, increase of intraocular pressure and vitreous hemorrhage as well as has low patient compliance. Abzyme Therapeutics LLC proposes to develop a new therapeutic for self-administrable noninvasive topical delivery to inhibit abnormal angiogenesis in the retina and choroid. The anti-neovascularization therapeutic for AMD treatment will be designed to overcome the retinal and choroidal barriers such that the therapeutic can be delivered in the form of eye drop. Active anti-angiogenesis therapeutics will reach the VEGF target in the vitreous humor via transferrin receptor (TfR) mediated transcytosis and transcorneal transport. In Phase I, human single domain high affinity anti-VEGF neutralizing nanobodies and bispecific VEGF/TfR nanobodies with low affinity to TfR and high affinity to VEGF will be produced. The accumulation of nanobodies in the vitreous humor and retina will be determined in a mouse model that receives topical eye drops. In Phase II, the anti-neovascularization activity of transferrin receptor- mediated anti-VEGF therapeutics will be characterized and validated in animal AMD models pursuing the IND application.